Cognitive flexibility is the ability to modify pre-established behaviors, habits, learned contingencies and patterns of thought based on new information from a changing environment. This ability is significantly impaired in several psychiatric disorders that include psychosis, neurodevelopmental, and affective disorders. Cognitive dysfunction is not only an important contributor to chronicity and recurrence of symptoms; it is also a predictor of poor treatment outcome, and the cognitive impairment itself is often resistant to improvement by pharmacological or other interventions. Thus, novel approaches aimed specifically at improving this component of psychopathology are needed. But progress has been hindered by a lack of clear understanding of the nature of such cognitive deficits and the neural substrates that underlie them. This R21 addresses a novel mechanism regulating cognitive function in the orbitofrontal cortex (OFC). Our lab has been using a highly translational test of cognitive flexibility in rats, the attentional set-shift test (AST) that, amongst other parameters, assesses reversal learning capability and factors that influence it. We have shown that reversal learning performance is compromised by chronic intermittent cold stress (CIC). These detrimental effects of CIC are mimicked by serotonin depletion, and can be prevented or reversed by SSRI administration. Most recently, we showed that 5HT2A receptors in the OFC exert facilitating effects on reversal learning under basal conditions. In the course of another project aimed at investigating the role of neuroinflammatory signals in stress-induced cognitive deficits, we found, contrary to our expectations, that exogenous administration of low levels of the cytokine interleukin 6 (IL6) into the orbitofrontal cortex improves the reversal learning deficit induced by CIC stress, and that blockade of IL6 signaling, by giving either a neutralizing IL6 antibody or an inhibitor of the JAK/STAT3 pathway into the OFC, worsens reversal learning performance on the AST. These surprising observations led us to hypothesize that basal IL6/STAT3 signaling in the OFC is required for optimal reversal learning capability. In addition, we suggest as a possible molecular mechanism, that IL6 and/or STAT3 interact with serotonergic neurotransmission, possibly at the level of the 5HT2A receptor, to facilitate cognitive performance. To test these hypotheses, in Aim 1 we will investigate whether the beneficial effects of the SSRI citalopram on reversal learning are prevented by IL6 blockade. Reciprocally, in Aim 2, we will explore whether the beneficial effects of IL6 on reversal learning in the OFC require serotonin. In aim 3, we will begin to investigate the molecular mechanisms by which these effects are manifest, by examining potential interactions of IL6/STAT3 with 5HT2A receptor signaling in neuronal cell lines and cortical cells in vitro. These studies will generate new data toward a future proposal to explore more fully the interactions of IL6/STAT3 signaling with classic neurotransmitters and receptors in the prefrontal cortex, including serotonin; and the potentially beneficial effects of targeting these interactions as novel therapeutic strategies specifically for the treatment of cognitive dysfunction.